Transcription of genes in mammalian cells is regulated by complex mechanisms wherein interactions of the regulatory DNA sequences with trans-acting DNA binding proteins play a central role. In the context of the regulation of transcription, genes encoding interferons (IFNs) represent a feature common to many of the cytokine genes; transcription of those genes is induced in a transient manner following various extra-cellular signals. It has been well documented that transcription of the genes for IFN-.alpha. and IFN-.beta. is efficiently induced by viruses in a variety of cells, while that of the gene encoding IFN-.gamma. is induced in T lymphocytes (T cells) following mitogenic stimulation (for a review, see Weissmann and Weber, 1986; Taniguchi, 1988).
IFN-.beta., a cytokine that was originally identified for its potent antiviral activity, also appears to play a crucial role in controlling cell growth and differentiation. In this regard, beside viruses and poly(rI):poly(rC) which are the well known inducers of IFN-.beta. gene, many of the cytokines such as colony stimulating factor-1 (CSF-1) (Moore et al., 1984; Warren and Ralf, 1986; Resnitzky et al., 1986), tumor necrosis factor (TNF) (Onozaki et al., 1988), platelet-derived growth factor (PDGF) (Zullo et al., 1985) and IFNs (Kohase et al., 1987) also appear to induce IFN-.beta. in certain cells, suggesting that they may transduce similar or identical signals in the target cells.
The IFN-.beta. gene induction by viruses and poly(rI):poly(rC) has been shown to occur at the transcriptional level (Raj and Pitha, 1983; Ohno and Taniguchi, 1983; Dinter et al., 1983; Zinn et al., 1983). Thus cis-acting DNA sequences functioning as inducible enhancers have been identified within the 5'-flanking region of the human IFN-.beta. gene (Fujita et al., 1985, 1987; Goodbourn et al., 1985; Dinter and Hauser, 1987). The inducible enhancer region (i.e. -65 to -105 with respect to the CAP site) contains repetitive hexanucleotide units some of which indeed function in the induced-activation of transcription when multimerized (Fujita et al., 1987). We have identified in mammalian cells such as mouse L929 cells and human cells, a factor, IRF-1, which specifically binds to the IFN-.beta. regulatory sequences, as well as to the functional, repeated hexanucleotide sequences; (AAGTGA).sub.4. We have found that IRF-1 plays an essential role in virus-induced activation of IFN-.beta. gene transcription by interacting with the identified cis-elements.